DR BENDELL: So this is bringing in a new pathway that we’re all going to have to learn about, if we haven’t learned about it already, which is the cMET pathway. So cMET is a receptor that sits on the outside of cancer cells. And it has a tyrosine kinase effect that sends signals into the nucleus to tell its cells to divide, to make it very simplified.
The ligand that binds to the cMET receptor to activate it is called HGF, or hepatocyte growth factor. So 2 different names for the ligand and the receptor in the system. And we know that c-MET and high c-MET levels across multiple tumor types is associated with a bad prognosis. We also know that cMET interacts with both the EGFR pathway as well as the VEGF pathway. So we’ve seen data from other tumor types, particularly lung cancer, where combining anti-EGFR therapy with cMET therapy may do well for patients who are what we call MET high.
So we’ve also seen with the gastric cancer data that this was a drug called rilotumumab, which is an anti-HGF drug. It’s an anti-HGF antibody. So, just like bevacizumab, it binds to the ligand of the system. And so in a very small randomized Phase II study, they took patients with first-line metastatic gastric cancer and randomized them to chemotherapy plus or minus rilotumumab.
And what was interesting is when they took the MET-high patients — and so MET high is an IHC test where they look at it just like HER2 IHC. They look at it under the microscope, and they look for the percent of cells that are high in expression. And we’ve seen that for those high patients, they seem to get a benefit in both progression-free and overall survival using the anti-HGF antibody. So that’s now been taken into a randomized Phase III study called RILOMET-1.
We’ve also seen that other agents are in play here as well. So there is a drug called onartuzumab. And the way that you remember it is it’s a one-armed antibody, so like the one-armed man from The Fugitive is. Onartuzumab is an anti-cMET receptor antibody. And so they’re looking at that in the combination with FOLFOX plus or minus onartuzumab for MET-high patients.
DR LOVE: Can I just clarify, because that’s so-called MetMAb. Correct?
DR BENDELL: Correct.
DR LOVE: And I know your colleague — I was actually just talking to him a couple of days ago, Dave Spigel, who’s been very involved with this in lung cancer.
DR BENDELL: Correct.
DR LOVE: What’s the difference in terms of mechanism of rilotumumab versus onartuzumab, MetMAb?
DR BENDELL: Sure. Sure. So rilotumumab will bind to HGF, so binds the ligand to the receptor, whereas MetMAb, or onartuzumab, binds to the receptor itself. So just like we have been talking about bevacizumab and ramucirumab, so bevacizumab binds to the ligand. Ramucirumab binds to the receptor. So that’s the same kind of…
DR LOVE: What kind of tolerability issues occur with both?
DR BENDELL: So, interestingly, when you look at onartuzumab, it’s relatively well tolerated. Maybe some increases in swelling that’s been seen, but not a lot of added toxicity — knock wood — that we’ve seen with these agents.
There’s another agent out there that binds. It’s an oral drug that we think binds to the tyrosine kinase of c-MET that’s been in testing in lung cancer, called tivantinib, or ARQ 197. And that’s inside the cell.
DR LOVE: TKI.
DR BENDELL: Exactly.
DR LOVE: Just kind of curious, globally, Charlie, looking at this research and, also, this type of research, is this where we’re heading in general in GI cancers? And do you think this is the right direction?
DR FUCHS: Absolutely. I think it’s very exciting. Gastric cancer in particular lends itself to this concept, because in contrast to some of the GI cancers, it’s mutationally pretty bland. There aren’t a lot of mutations. But what you see are amplifications of various things. We’ve obviously heard about HER2, but also cMET, and among other targets. So these may lend themselves to the various targeted agents. So I anticipate, either through immunohistochemistry or through analyses of copy number, FISH, otherwise, that we’ll be able to segregate out these patients, initially HER2, maybe cMET, among others, and really define targeted agents that best suit them.
DR LOVE: So I’m curious also, Philip, what your thoughts are about this. And for oncologists, it’s hard to know when to start paying attention. Clearly, when you have a situation where people have responses that are occurring to novel agents, that’s one thing. But at this earlier stage, it’s kind of hard to separate the hype from the hope, so to speak. What about c-MET as a target?
DR PHILIP: Certainly, the data that we have so far make us very interested in terms of the validity of targeting this pathway. If we look at failures of targeted therapies like EGFR, just to use that as an example in this disease, we didn’t really see enough in terms of early responses even to make us interested in that pathway. And certainly there were trials, Phase II/Phase III trials, that failed. But here, we’re seeing an early signal of benefit from targeting this pathway. And I would think that this is going to increase our treatment options.
And, as you can see here, there’s focus on the front line, where in gastric cancer, really, if we see a signal, it will be seen more in the front line, because we combine it with chemotherapy also.